High-grade gliomas have one of worst prognoses among all types of human cancers and the efficacy of current therapies remains poor. We are interested in the role of the NF-?B transcription factor family as a key regulator of glioma cancer stem cells (CSCs), which are proposed to give rise to tumor cell heterogeneity and invasive growth. To-date, anti-NF-?B cancer therapy strategies have focused on targeting canonical NF-?B (RelA/IKK) activation without consideration of the non-canonical NF-?B pathway (RelB/IKK?). Based on our recent findings that RelB promotes oncogenesis in mesenchymal glioma (Lee et al. PLOS One, 2013), we argue that there is a critical need to understand how specific NF-?B signaling pathways contribute to tumor initiation/ progression. Specifically, we propose that canonical and non-canonical NF-?B signaling may be particularly important in different glioma subtypes, as well as distinct cancer stem cell populations. Recent studies suggest an intimate relationship between transforming growth factor (TGF)-induced epithelial-to-mesenchymal transition (EMT) and CSCs survival and invasion. However, the role of EMT and CSC survival in glioma is unclear. Based on preliminary data, we propose to 1) determine which NF-?B proteins and upstream signaling pathways are activated in different glioma subtypes and CSCs; 2) evaluate the role of specific NF-?B proteins in promoting self-renewal and pluripotency in distinct CSC populations; and 3) test the effects of inhibiting IKK/NF-?B on glioma CSC survival, invasion and tumor growth in vivo. A better understanding of the mechanisms regulating glioma stem-cell self-renewal and differentiation will not only reveal new insights into glioma tumor biology, but will also facilitate identifying novel approache to target the key cells responsible for tumor heterogeneity and treatment resistance.